BACKGROUND:Low temperatures have detrimental effects on the human cardiovascular system,with a higher prevalence of hypertension and related cardiovascular diseases,especially among people living in cold climates.Transient receptor potential M8(TRPM8)is often recognized as a physiological sensor of environmental cold,and glutamate receptor-3(GLR-3)/glutamate receptor ionotropic,kainate 2(GluK2)is also cold-sensitive.However,the specific molecular mechanisms of cold-associated TRPM8 and GLR-3/GluK2 in regulating hypertension remain puzzling.OBJECTIVE:Through a review of the literature in this field,to find out the general pattern of TRPM8 and GLR-3/GluK2 in regulating the body's cold response,as well as the specific mechanism of action in hypertension,thereby providing a theoretical basis for subsequent research on the treatment of hypertension based on cold-stimulation-related targets,and further expanding the new ideas and methods for the treatment of hypertension.METHODS:We searched,reviewed and screened the relevant literature on"cold stimulation,TRPM8,GLR-3/GluK2 and hypertension"to lay the theoretical foundation for the analysis of the whole article.Comparative analysis method,through reading and analyzing the obtained literature,comparing the similarities and differences between the literature,was performed to provide reasonable theoretical support for the argument.Through further comparative analysis of the literature,the relationship between the relevant indicators was clarified,and the ideas were clarified for the analysis of the full text.RESULTS AND CONCLUSION:(1)TRPM8 can be activated by cold and mainly mediates cool temperature perception in mammals.Its activation can trigger neurogenic inflammatory response and indirectly affect the inflammatory process.Abnormal TRPM8 signal can lead to excessive activation of immune cells,which is significantly associated with the occurrence and development of hypertension.(2)The activation threshold of GLR-3/GluK2 is lower than that of TRPM8,which may preferentially respond to noxious cold stimulation rather than ordinary cool temperature.In cold environment,GLR-3/GluK2 activation enhances sympathetic nerve excitability by regulating interneuron signal transduction and causes peripheral vascular constriction.Long-term effects can lead to increased peripheral vascular resistance.To conclude,TRPM8 and GLR-3/GluK2 are involved in the interaction of the nerve-immune-vascular system by sensing different cold stimuli.Abnormal TRPM8 signaling indirectly promotes the progression of hypertension through inflammation and immune dysregulation,while GLR-3/GluK2 directly exacerbates vascular constriction and resistance by enhancing sympathetic nerve activity.The combination of the two factors may constitute the key molecular mechanism of the occurrence and development of hypertension in cold environment,and provide a potential target for the intervention of cold-related cardiovascular diseases.

BACKGROUND:Low temperatures have detrimental effects on the human cardiovascular system,with a higher prevalence of hypertension and related cardiovascular diseases,especially among people living in cold climates.Transient receptor potential M8(TRPM8)is often recognized as a physiological sensor of environmental cold,and glutamate receptor-3(GLR-3)/glutamate receptor ionotropic,kainate 2(GluK2)is also cold-sensitive.However,the specific molecular mechanisms of cold-associated TRPM8 and GLR-3/GluK2 in regulating hypertension remain puzzling.OBJECTIVE:Through a review of the literature in this field,to find out the general pattern of TRPM8 and GLR-3/GluK2 in regulating the body's cold response,as well as the specific mechanism of action in hypertension,thereby providing a theoretical basis for subsequent research on the treatment of hypertension based on cold-stimulation-related targets,and further expanding the new ideas and methods for the treatment of hypertension.METHODS:We searched,reviewed and screened the relevant literature on"cold stimulation,TRPM8,GLR-3/GluK2 and hypertension"to lay the theoretical foundation for the analysis of the whole article.Comparative analysis method,through reading and analyzing the obtained literature,comparing the similarities and differences between the literature,was performed to provide reasonable theoretical support for the argument.Through further comparative analysis of the literature,the relationship between the relevant indicators was clarified,and the ideas were clarified for the analysis of the full text.RESULTS AND CONCLUSION:(1)TRPM8 can be activated by cold and mainly mediates cool temperature perception in mammals.Its activation can trigger neurogenic inflammatory response and indirectly affect the inflammatory process.Abnormal TRPM8 signal can lead to excessive activation of immune cells,which is significantly associated with the occurrence and development of hypertension.(2)The activation threshold of GLR-3/GluK2 is lower than that of TRPM8,which may preferentially respond to noxious cold stimulation rather than ordinary cool temperature.In cold environment,GLR-3/GluK2 activation enhances sympathetic nerve excitability by regulating interneuron signal transduction and causes peripheral vascular constriction.Long-term effects can lead to increased peripheral vascular resistance.To conclude,TRPM8 and GLR-3/GluK2 are involved in the interaction of the nerve-immune-vascular system by sensing different cold stimuli.Abnormal TRPM8 signaling indirectly promotes the progression of hypertension through inflammation and immune dysregulation,while GLR-3/GluK2 directly exacerbates vascular constriction and resistance by enhancing sympathetic nerve activity.The combination of the two factors may constitute the key molecular mechanism of the occurrence and development of hypertension in cold environment,and provide a potential target for the intervention of cold-related cardiovascular diseases.

OBJECTIVE To develop and validate interpretable machine learning models for predicting the risk of medication-related osteonecrosis of the jaw （MRONJ） and surgical outcomes， thereby providing quantitative support for MRONJ risk assessment and treatment decision-making.METHODS Two study cohorts were established. Cohort A adopted a nested case-control study design to develop a predictive model for the risk of MRONJ onset. Cohort B comprised patients with MRONJ from Cohort A who underwent surgical treatment and met the follow-up eligibility criteria， and employed a prospective follow-up cohort study design to develop a predictive model for the efficacy of MRONJ surgery. After missing-data processing， variable standardization， and encoding， predictive features were selected using the least absolute shrinkage and selection operator （LASSO） regression， and collinearity was assessed using the variance inflation factor （VIF）. Random Forest （RF）， eXtreme Gradient Boosting （XGB）， Multi-layer Perceptron （MLP）， Support Vector Machine （SVM）， and Gaussian Naive Bayes （NB） models were subsequently developed using the selected features. Hyperparameter optimization and internal performance evaluation were performed using two-level nested cross-validation repeated 20 times. In Cohort B， the synthetic minority over-sampling technique （SMOTE） was applied within the inner training folds to address class imbalance. Model performance was comprehensively evaluated using the receiver operating characteristic （ROC） curve， the precision-recall （PR） curve， calibration curve， and decision curve analysis （DCA）. Shapley additive explanations （SHAP） were used to quantify the relative contributions of individual clinical features to model predictions.RESULTS Seven clinical features， including alkaline phosphatase and tooth extraction， were retained for Cohort A； whereas eight clinical features， including age and duration of medication use， were retained for Cohort B. In Cohort A， the area under the ROC curve， the area under the PR curve， Brier score， sensitivity， and specificity of the RF model were 0.94， 0.92， 0.09， 0.92， and 0.85， respectively； the corresponding values in Cohort B were 0.93， 0.93， 0.12， 0.83， and 0.93， respectively. The results of calibration curves and DCA indicated that the RF models achieved favorable calibration and clinical net benefit， with VIF values for all variables below 5. SHAP visualization results showed that alkaline phosphatase， tooth extraction， and cumulative drug dose made substantial contributions to MRONJ risk prediction in Cohort A， whereas age， duration of medication use， and MRONJ stage contributed substantially to surgical outcome prediction in Cohort B.CONCLUSIONS The RF-based models for predicting MRONJ risk and surgical outcomes demonstrated good discrimination， accuracy of probabilistic predictions， and potential clinical utility during internal validation. These models may provide decision support for comprehensive MRONJ risk management and individualized clinical decision-making. However， external validation in independent， multicenter， and geographically diverse cohorts is still required.

In order to explore the effect of PGD2/DP1 receptor pathway on the expression of cyto-kines and injury-related factors in Escherichia coli(E.coli)induced bovine bone marrow derived macrophages,an in vitro model of E.coli induced bovine bone marrow derived macrophages was established.The effects of DP1 receptor agonist on phagocytosis and killing ability,mRNA expres-sion,secretion of pro-inflammatory cytokines(TNF-α,IL-1β)and activation of signaling pathway(MAPK,NF-κB)in cow bone marrow derived macrophages induced by E.coli were examined.The results showed that compared with the E.coli infection group,the phagocytosis and killing ability of BW-245C+E.coli group and 15 d-PGJ2+E.coli group were enhanced(P＜0.01).Compared with the blank control group,mRNA expression was at a higher level(P＜0.001),and the secre-tion of pro-inflammatory cytokines(TNF-α,IL-1β)was significantly increased after adding E.coli solution.The mRNA expression of BW-245C+E.coli group and 15 d-PGJ2+E.coli group were significantly decreased(P＜0.001),and the secretion of pro-inflammatory cytokines(TNF-α,IL-1β)was significantly decreased(P＜0.001).and signaling pathway(MAPK,NF-κB)were sig-nificantly down-regulated(P＜0.001).This study showed that DP1receptor agonist plays an inhib-itory role in the inflammatory response of cow bone marrow-derived macrophages induced by E.coli.This finding provides a potential target for future treatment of cow endometritis,laying the foundation for the development of novel anti-inflammatory treatment strategies.

The placenta is a temporary organ connecting the mother and fetus during embryonic development, facilitating fetal growth by transporting oxygen and nutrients and removing waste products. Placental dysfunction can lead to severe maternal and fetal complications, with potential long-term health consequences. Therefore, monitoring placental function is a critical aspect of prenatal care. Traditional clinical assessments rely on indirect methods, but functional quantitative magnetic resonance imaging (qMRI) offers a new approach. The use of qMRI enables direct evaluation of the oxygenation in the placenta and fetal organs, providing precise quantitative metrics. This technology holds promise for early detection and intervention before the onset of placental failure or fetal injury. This article reviews the latest advancements in MRI technology for evaluating placental and fetal multi-organ oxygenation.

Objective:To evaluate the effect of thunder-fire moxibustion combined with fire-dragon cupping on patients with acute peripheral facial paralysis with co-morbid anxiety and depression.Methods:A total of 80 patients with acute peripheral facial paralysis with co-morbid anxiety and depression were selected and divided into two groups according to the random number table method,with 40 patients in each group.In the control group,acupuncture therapy combined with routine care was given;in the observation group,thunder-fire moxibustion and fire-dragon cupping therapy were added.Both groups were treated once a day,6 times a week,with 1 d of rest,for 4 consecutive weeks(a total of 24 treatments).The House-Brackmann(H-B)grading,facial clinimetric evaluation(FaCE),self-rating anxiety scale(SAS),and self-rating depression scale(SDS)were used before and after the intervention to evaluate the facial nerve function,quality of life,mental health,and clinical efficacy of the two groups.Results:After treatment,patients in both groups showed improvement in H-B grading,scores of all dimensions of the FaCE scale,and SAS and SDS scores compared to those before treatment,and the differences within the groups were statistically significant(P<0.05).After treatment,the total effective rate was 95.0%in the observation group and 75.0%in the control group,and the difference between the two groups was statistically significant(P<0.05).After treatment,the H-B grading of the observation group was better than that of the control group(P<0.05);the scores of all dimensions of the FaCE scale and SAS and SDS scores of the observation group were better than those of the control group(P<0.05).Conclusion:Adding thunder-fire moxibustion and fire-dragon cupping therapy to acupuncture and routine care can promote the recovery of facial nerve function,reduce anxiety and depression,and improve the patients'living standard,and thus is suitable for popularization and application.

Objective To assess the intervention effect of nicotinamide mononucleotide (NMN) on the mouse model of hematotoxicity induced by subacute benzene exposure. Methods Benzene exposure and NMN intervention were adopted in a 2×2 factorial design, as benzene exposure and non-exposure, and NMN intervention and non-intervention. Male specific pathogen-free C57BL/6J mice were randomly assigned to negative control group, NMN control group, simple benzene exposure group and NMN intervention group, with 12 mice in each group. Benzene exposure of mice in simple benzene exposure group and NMN intervention group was conducted by dynamic inhalation of benzene at a concentration of 325 mg/m³ for six hours per day, five days per week for four weeks (28 days). Mice in the negative control and NMN control group inhaled clean air. During benzene exposure, mice in the NMN control group and NMN intervention group received NMN in drinking water at a dose of 300 mg/kg body weight. Peripheral blood samples of mice were collected for complete blood count analysis and calculation of composite inflammatory indices after 28 days. Results Interaction analysis showed that the counts of peripheral white blood cell, neutrophil, lymphocyte, and platelet of mice in the simple benzene exposure group were lower than those in the negative control group (all P<0.05). Neutrophil and platelet counts in the NMN intervention group were higher than those in the simple benzene exposure group (all P<0.05). The results of main effect analysis showed that the monocyte count of peripheral blood, systemic inflammatory index, systemic inflammatory response index, neutrophil/lymphocyte ratio and platelet/lymphocyte ratio of mice in the benzene exposure group increased (all P<0.05), and the basophil count and lymphocyte/monocyte ratio decreased (all P<0.05), compared with the control group. Conclusion Oral NMN alleviates subacute benzene-induced decreases in peripheral neutrophil and platelet counts in mice. This protective effect may be related to the targeted intervention of NMN on mitochondrial energy metabolism disorder and oxidative damage induced by benzene exposure in male mice.

In order to study the effects of prostaglandin D2(PGD2)on cow bone marrow-derived macrophages induced by E.coli,cultured cow bone marrow-derived macrophages were taken as the research object.The effects of endogenous and exogenous PGD2 on the secretion and phagocytosis of E.coli induced proinflammatory cytokines(IL-1β,IL-6 and TNF-α)in macrophages were ana-lyzed.The results showed that the synthesis of PGD2 in macrophages induced by E.coli is depend-ent on the natural pattern recognition receptors TLR2,TLR4 and NLRP3.Inhibition of endogenous PGD2can down-regulate the secretion of pro-inflammatory cytokines(IL-1β,IL-6 and TNF-α)in E.coli induced macrophages(P＜0.001),and inhibition of endogenous PGD2 can enhance the kill-ing function of macrophages to a certain extent(P＜0.01).In addition,exogenous PGD2 could up-regulate the secretion of pro-inflammatory cytokines(IL-1β,IL-6 and TNF-α)in macrophages af-ter E.coli stimulation(P＜0.01),and exogenous PGD2 could weaken the killing function of mac-rophages within a certain concentration range(P＜0.01).Results indicated that PGD2 had certain effects on the secretion of cytokines and phagocytosis and killing function of macrophages induced by E.coli.

In order to explore the effect of PGD2/DP1 receptor pathway on the expression of cyto-kines and injury-related factors in Escherichia coli(E.coli)induced bovine bone marrow derived macrophages,an in vitro model of E.coli induced bovine bone marrow derived macrophages was established.The effects of DP1 receptor agonist on phagocytosis and killing ability,mRNA expres-sion,secretion of pro-inflammatory cytokines(TNF-α,IL-1β)and activation of signaling pathway(MAPK,NF-κB)in cow bone marrow derived macrophages induced by E.coli were examined.The results showed that compared with the E.coli infection group,the phagocytosis and killing ability of BW-245C+E.coli group and 15 d-PGJ2+E.coli group were enhanced(P＜0.01).Compared with the blank control group,mRNA expression was at a higher level(P＜0.001),and the secre-tion of pro-inflammatory cytokines(TNF-α,IL-1β)was significantly increased after adding E.coli solution.The mRNA expression of BW-245C+E.coli group and 15 d-PGJ2+E.coli group were significantly decreased(P＜0.001),and the secretion of pro-inflammatory cytokines(TNF-α,IL-1β)was significantly decreased(P＜0.001).and signaling pathway(MAPK,NF-κB)were sig-nificantly down-regulated(P＜0.001).This study showed that DP1receptor agonist plays an inhib-itory role in the inflammatory response of cow bone marrow-derived macrophages induced by E.coli.This finding provides a potential target for future treatment of cow endometritis,laying the foundation for the development of novel anti-inflammatory treatment strategies.

Objective:To investigate the distribution of CGG repeat numbers in the FMR1 gene among reproductive-age women in China, providing data reference for carrier screening and genetic counseling of Fragile X syndrome. Methods:This cross-sectional study recruited 16 610 reproductive-age women from 12 medical institutions between July 2022 and October 2023. Peripheral venous blood samples (3 mL) were collected, and genomic DNA was extracted. The number of CGG repeats in the FMR1 gene was determined using the triplet-primed polymerase chain reaction (TP-PCR) combined with capillary electrophoresis technology. Statistical analyses were performed to assess the prevalence and distribution of CGG repeat expansions. Results:Among 16 610 women of childbearing age, 5 684 (34.220%) women had the same number of CGG repeats in the two alleles of FMR1 gene, and 10 926 (65.780%) women had different numbers of repeats in the two alleles. Among the 33 220 FMR1 alleles in 16 610 women of reproductive age, the most common CGG repeat numbers were 29 [48.645% (16 160/33 220)] and 30 [26.276% (8 729/33 220)], while the most frequent CGG genotype was CGG 29/29 [24.726% (4 107/16 610)]. The CGG repeat numbers of FMR1 gene were normal in 16 498 women (99.326%). Among the 112 women (0.674%) with CGG repeat abnormities, 96 (0.578%) women were classified as intermediate carriers, 15 (0.090%) as premutation carriers, and 1 (0.006%) as a full mutation carrier, whose CGG genotype was (36, >200). Conclusion:In the general reproductive-age female population in China, the normal CGG repeat numbers of the FMR1 gene account for 99.326%, while the intermediate carrier rate is 0.578%, and the combined carrier rate of the premutation and full mutation types is 0.096%.